17-(lower aliphatic mono-unsaturated hydrocarbon)-17beta-hydroxy-2-oxaestra-4, 9(10)-dien-3-ones, 11-dehydro compounds corresponding and esters thereof



United States PatentO 3,405,140 17 (LOWER ALIPHATIC MONO UNSATURATED HYDROCARBON) 17,8 HYDROXY 2 OXAES- TRA 4,9(10) DIEN 3 ONES, 11 DEHYDRO COMPOUNDS CORRESPONDING AND ESTERS THEREOF Raghael Pappo, Skokie, and Christopher J. Jung, Morton rove, Ill., assiguors to G. D. Searle & 'Co., Chicago, Ill., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 479,318, Aug. 12, 1965. This application July 18, 1966, Ser. No. 565,707

9 Claims. (Cl. 260-3432) ABSTRACT OF THE DISCLOSURE 17-(lower aliphatic mono-unsaturated hydrocarbon)- 17fi-hydroxy-2-oxaestra-4,9 10)-dien-3-ones, ll-dehydro compounds corresponding and esters thereof preparable by utilizing as starting materials the corresponding A compounds and useful in view of their hormonal properties, e.g., progestational, anabolic and androgenic. Thus, the A compounds are contacted with bromine in the presence of a suitable organic base to produce the corresponding A dienes. The A compounds are produced by an acid or base catalyzed rearrangement of said dienes to the corresponding A compounds followed by treatment with a peroxidizing agent, cleavage of the produced epoxy compounds and dehydration of the hydroxy intermediates prepared thereby.

This application is a continuation-in-part of our copending application Ser. No. 479,318, filed Aug. 12, 1965, now abandoned.

The present invention is concerned with novel dienoic and trienoic lactones characterized by an unsaturated hydrocarbon substituent at the 17 position and, more particularly, with 17-(1ower aliphatic mono-unsaturated hydrocarbon)-l7fi-hydroxy-2-oxaestra 4,9(10) -dien-3-ones, the ll-dehydro compounds corresponding and the esters thereof which are represented by the following structural formula wherein n is a positive integer less than 8.

and

The compounds of the following formula wherein R is hydrogen or a lower alkanoyl radical, X represents a lower aliphatic mono-unsaturated hydrocarbon radical having the unsaturated linkage adjacent to the point of attachment at the 17 position and the dotted line indicates an optional 11, 12 doublebond, constitute one preferred embodiment of this invention. Specific examples of the radicals contemplated are ethynyl, vinyl, 1- propynyl, l-propenyl, l-heptynyl, l-heptenyl, i.e., those of the following formula CEC CnH2n+l wherein n is a positive integer less than 6 and the dotted line indicates that the unsaturated linkage is alternatively doubly or triply bonded.

Suitable starting materials for the manufacture of the instant compounds are the 17-substituted 2-oxaestr-5(10)- en-3-ones described in US. Patent 3,246,014. When those A compounds are contacted with bromine in the presence of a suitable organic base, there are produced the corresponding A substances. As a specific example,

pyridine is contacted with a carbon tetrachloride solution of bromine at room temperature to yield l7a-ethynyl- 17,8-hydroxy-2-oxaestra-4,9 10) -dien-3-one.

The instant A compounds are conveniently produced by a process involving, as the first step, rearrangement of the 4(5) and 9(10) double bonds of the aforementioned dienes' to the 5(10) and 9(11) positions, respectively. That rearrangement is effected under the influence of either an acidic or an alkaline catalyst. As a specific example, 17a-ethynyl-17fl-hydroxy-2-oxaes-tra-4, 9(10)-dien-3-one in methanol is contacted with aqueous sodium hydroxide to yield 17a-ethynyl-17p-hydroxy-2- oxaestra-5(10),9(l1)-dien-3one. Reaction of those 5(10), 9(11)-dienes with a peroxidizing agent such as an organic peracid results in a mixture of the corresponding 9a,11ozepoxide and 5,9,103-epoxide. When l7oa-ethyny1-1718-hydroxy-2-oxaestra-5(10),9(11)-dien-3-one is allowed to react with m-chloroperbenzoic acid in methylene chloride, there is obtained a mixture of 911,1lot-epoxy-17a-ethynyll7fi-hydroxy-2-oxaestr-5(10)-en-3-one and 5,8,10p-epoxyl7a-ethynyl-l7fi-hydroxy-2-oxaestr-9 11 )-en-3-one. When those epoxides are cleaved, typically by heating with a suitable organic amine, the corresponding lla-hydroxy- 4,9(l0)-diene and 10fi-hydroxy-4,9(l1)-diene are obtained. A mixture of 911,1la-epoxy-17a-ethynyl-17B-hydroxy-2-oxaestr-5(10)-en-3-one and 55,1013-epoxy-17uethynyl-17fl-hydroxy-2-oxaestr-9(l1)-en-3-one dissolved in pyridine is heated withtriethylamine to afford a mixture of 17a-ethynyl-11u,17;3-dihydroxy 2 oxaestra 4,9(10)- dien-3-one and l7a-ethynyl-10fl,l7fl-dihydroxy-2-oxaestra-4,9(11)-dien-3-one. Dehydration of either the IOB-hydroxy or lla-hydroxy intermediate or a mixture thereof is effected by heating with a suitable acid catalyst. The latter mixture in benzene is thus heated with p-toluenesulfonic acid to yield 17a-ethyny1-17B-hydroxy-2-oxaestra- 4,9 10) ,1 1-trien-3 -one and 17a-ethynyl-17,3-l1ydroxy-2- oxaestra-1(l0),4,9(11)-trien-3-one.

The instant l7a-alkenyl compounds are alternatively produced by partial reduction of the corresponding 17aalkynyl substances. That process is specifically illtistrated by the hydrogenation at atmospheric pressure and room temperature, utilizing a palladium-on-carbon catalyst, of 17a ethynyl 17B hydroxy 2 oxaestra-4,9()- dien 3 one to yield 175 hydroxy 2 oxa-17a-vinylestra-4,9( l0)-dien-3-one.

The reaction of the instant 17-hydroxy compounds with a lower alkanoic acid anhydride or halide, preferably in the presence of a suitable acid acceptor, produces the corresponding 17-(lower alkanoates). The aforementioned 17a ethynyl 17,8 hydroxy 2 oxaestra 4,9(10)-dien- 3-one is thus heated with acetic anhydride and pyridine to afford 17/3 acetoxy 17a-ethynyl-2-oxaestra-4,9(10)-dien- 3-one.

The compounds of the present invention exhibit valuable pharmacological properties. They are hormonal agents, for example, as is evidenced by their progestational activity. Thus, they possess the ability to effect proliferation of the uterine epithelium. They exhibit also anabolic and androgenic activity.

The following examples describe in detail certain of the compounds illustrative of the present invention and methods which have been devised for their manufacture. The invention, however, is not to be construed as limited thereby either in spirit or in scope since it will be apparent to those skilled in the art that many modifications both in materials and methods may be practiced without departing from the purpose and intent of the disclosure. In the examples hereinafter detailed, temperatures are given in degrees centigrade C.) and quantities of materials in parts by weight except as otherwise noted.

Example 1 To a solution of one part of 17cc ethynyl l7B-hydroxy- 2-oxaestr-5(l0)-en-3-one in parts of pyridine is added, at room temperature over a period of about 3 minutes, 6.72 parts by volume of a carbon tetrachloride solution containing 0.59 part of bromine. The reaction mixture is allowed to stand at room temperature overnight, then is concentrated to a small volume by distillation at room temperature under reduced pressure. The residual mixture is diluted with Water, then is extracted with benzene. The benzene layer is separated, then is washed successively with dilute hydrochloric acid, water, dilute aqueous sodium hydroxide and water. Drying over anhydrous sodium sulfate followed by removal of the solvent under reduced pressure affords the crude product as a solid residue. Purification of that material by recrystallization from benzene results in 170: ethynyl 17 3 hydroxy 2 oxaestra 4, 9(l0)-dien-3-one, which melts at about 191196. This compound can be represented by the following structural formula Example 2 To a solution of 3 parts of 170: ethynyl 175 hydroxy- 2-oxaestra-4,9(10)-dien-3-one in 150 parts of pyridine is added 0.3 part of 5% palladium-on-carbon catalyst, and the resulting mixture is shaken with hydrogen at atmospheric pressure and room temperature until one molecular equivalent of hydrogen has been absorbed. The catalyst is removed by filtration, and the filtrate is stripped of solvent by distillation under reduced pressure to afford the crude residue. That material is triturated with benzene, then is dissolved in benzene, and that solution is stirred with aluminum silicate in order to remove suspended particles and color. The clarified and decolorized organic solution is partially concentrated, and the crystals which form are collected by filtration and dried to afford 17B hydroxy 2- oxa 17a vinylestra 4,9(10) dien-3-one, melting at about l'94198 and characterized by the following structural formula A mixture of one part of 170: ethynyl 17B hydroxy- 2 oxaestra 4,9(10) dien 3 one, 10 parts of acetic anhydride and 20 parts of pyridine is heated at 90100 for about 4 hours, then is cooled and poured carefully into a mixture of ice and water. The resulting aqueous solution is extracted with benzene, and the benzene layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, thus affording 17B acetoxy 17oz ethynyl 2 oxaestra 4,9 (10)-dien-3-one of the following structural formula OCOCHJ i' ozou Example 4 The substitution of an equivalent quantity of 17;?-

hydroxy 17a propynyl 2 oxaestr 5 (l0)-en-3-one in the procedure of Example 1 results in 176 hydroxy 2- oxa-17a-propynylestra-4,9(10)-dien-3-one.

Example 5 When equivalent quantities of I7B-hydroxy-2-oxa-17apropynylestra-4,9(l0)-dien-3-one and propionic anhydride are allowed to react according to the procedure of Example 3, there is obtained 2 oxa 17 8 propionoxy 17apropynylestra-4,9( 10) -dien-3 -one.

Example 6 The substitution of an equivalent quantity of 17fi-hydroxy 2 oxa 17a propynylestra 4,9(10) dien-3-one in the procedure of Example 2 results in 17 51 hydroxy-2- oxa-17a-propenylestra-4,9(10)-dien-3-one.

Example 7 To a solution of 9.5 parts of 17a-ethynyl-17B-hydroxy- 2-oxaestra-4,9(l0)-dien-3-one in 60 parts of methanol is added 6.4 parts by volume of a aqueous sodium hydroxide solution and the resulting reaction mixture is stored at room temperature in a nitrogen atmosphere for about 16 hours. At the end of that time, water is added, and the organic solvent is removed by distillation under reduced pressure. The pH is adjusted to approximately 8 by the addition of dilute hydrochloric acid and solid carbon dioxide. That aqueous mixture is washed with chloro- To a solution of 8.35 parts of l7a-ethynyl-17B-hydroxy- 2-oxaestra-5(10),9(11)-dien-3-one in 200 parts of methylene chloride is added, at about 6.04 parts of m-chloroperbenzoic acid. The reaction mixture is stored at approximately 0 for about 60-hou-rs, then is diluted with cold benzene and filtered. The filtrate is washed successively with cold dilute potassium bicarbonate and water, then dried over anhydrous sodium sulfate and stripped of solvent by distillation under reduced pressure. Crystallization of the resulting residue from ethyl acetate-benzene yields-a mixture of 911,1la-epoxy-l7a-ethynyl-l7 3-hydroxy 2 oxaestr-(10)-en-3-one and 5B,10B-epoxy- 17a-ethynyl-17B-hydroxy-2-oxaestr-9 11 )-en-3-one, melting at about 203210.

Example 9 To a solution of 3 parts of the mixture of 9a,11a-epoxy- 17a ethynyl 17 B-hydroxy-Z-oxaestr-S )-en-3 -one and 53,105 epoxy-17a-ethynyl-17fl-hydroxy-2-oxaestr-9(11)- en-3-one, obtained by the procedure described in Example 8, in 30 parts of pyridine is added 43.8 parts of triethylamine, and that reaction mixture is heated at the reflux temperature under nitrogen for about 40 minutes. Removal of the solvent by distillation under reduced pressure alfords a residue which is partitioned between water Example 10 To a solution of 1.96 parts of the mixture of 17aethynyl 110:,17/3 dihydroxy 2 oxaestra-4,9(l0-dien-3- one and 170: ethynyl 103,175 dihydroxy-Z-oxaestra- 4,9(l1)-dien-3-one, obtained according to the procedure of Example 9, in 440 parts of benzene is added 0.45 part of p-toluenesulfonic acid. The resulting reaction mixture is slowly distilled over a period of about 25 minutes, then is cooled and diluted with cold water. The diluted solution is stirred for about 5 minutes, at the end of which time the layers are separated, and the organic layer is washed successively with sodium hydroxide and water, then dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. The resulting residue is purified by crystallization from benzene to afford 17aethynyl 1713 hydroxy-Z-oxaestra-l (10),4,9(11)-trien-3- one, melting at about 214.5-2l7.5.

The benzene filtrates from the latter crystallization are concentrated to dryness, and the resulting residue is dissolved in 40 parts of methanol. To that solution is then added 20 parts of 5% aqueous sodium hydroxide, and the reaction mixture is stored at room temperature for about 4 hours. At the end of that time, the pH is adjusted to approximately 8 by the addition of solid carbon dioxide, and that mixture is extracted with chloroform. The chloroform solution is washed successively with aqueous potassium carbonate and water, then dried and stripped of solvent under reduced pressure to alford 17u-ethynyl-17B- hydroxy-2-oxaestra-4,9 10) ,1 1-trien-3-one, characterized by the following structural formula An additional quantity of 17a-ethynyl-17fl-hydroxy-2- oxaestra-4,9(10),11-trien-3-one is isolated from the latter alkaline aqueous solution by acidification with acetic acid followed by extraction with chloroform, washing of the chloroform solution successively with aqueous potassium carbonate and water, drying over anhydrous sodium sulfate and removal of the solvent by distillation under reduced pressure.

Example 11 To a solution of 3 parts of 17u-ethynyl-17fi-hydroxy-2- oxaestra-5(10),9(1l)-dien-3-one in parts of pyridine is added 0.3 part of 5% palladium-oncarbon catalyst, and the resulting mixture is shaken with hydrogen at atmospheric pressure and room temperature until one molecular equivalent of hydrogen has been absorbed. Removal of the catalyst by filtration aifords a filtrate, which is evaporated to dryness under reduced pressure. The resulting residue is dissolved in benzene, and that solution is clarified and decolorized by stirring with aluminum silicate. Partial concentration of the benzene solution results in crystallization of the product which is isolated by filtration and dried to afford, as the benzene solvate, 17fl-hydroxy-2-oxa 17a vinylestra-5(l0),9(ll)-dien-3- one, melting at about 82-89".

Example 12 By substituting an equivalent quantity of 17a-ethynyl- -hydroxy-2-oxaestra-4,9(10),11-trien-3-one and otherwise proceeding according to the processes of Example 2, there is obtained 17p-hydroxy-2-oxa-17a-vinylestra-4,9 (10),11-trien-3-one.

Example 13 By substituting an equivalent quantity of 17/3-hydroxy- 2 oxa 17oz propynylestra-4,9(10),l1-trien-3-one and otherwise proceeding according to the processes described in Example 3, there is produced 17/8-acetoxy-2-oxa-17upropynylestra-4,9( 10) ,1 1-trien-3-one.

Example 15 The substitution of an equivalent quantity of 17 8-hydroxy-2-oxa 17a propynylestra-4,9(10),11-trien-3-one in the procedure of Example 2 results in 17/3-hydroxy-2- oxa-17a-propenylestra-4,9 10 ,1 1-trien-3-one.

What is claimed is:

1. A compound of the formula wherein A is a lower mono-unsaturated aliphatic hydrocarbon radical, R is selected from the group consisting of hydrogen and a radical of the formula where A is a lower mono-unsaturated aliphatic hydro- 20 carbon radical and the dotted line indicates the optional presence of an 11,12 double bond. V

3. As in claim 1, a compound of the formula OH 25 A j -(lower alkynyl) 4. As in claim 1, a compound of the formula j --(lower alkcnyl) 5. As in claim 1, the compound which is 17a-ethynyl- 17fi-hydroxy-2-oxaestra-4,9( 10) -dien-3-one.

6. As in claim 1, the compound which is 17fi-hydroxy- 2-oxa-17 u-vinylestra-4,9( 10 -dien-3-one.

7. As in claim 1, the compound which is 17;8-acetoxy- 17u-ethynyl-2-oxaestra-4,9(10)-dien-3-one.

8. As in claim 1, the compound which is 17a-ethynyl- 17 fi-hydroxy-2-oxaestra-4,9 l0),1 1-trien-3-one.

9. As in claim 1, the compound which is 17fl-hydroxy- 17m-vinyl-2-oxaestra-4,9(l0),11-trien-3-one.

References Cited UNITED STATES PATENTS 3,246,014 4/1966 Jung et a1. 260-3432 JAMES A. PATTEN, Primary Examiner. 

